Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation.

DNAJC3, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco-Sjogren and Wolcott-Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in DNAJC3 was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3 [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.

Randomized controlled trial: a pilot study of a psychoeducational intervention for fatigue in patients with quiescent inflammatory bowel disease.

INTRODUCTION: Fatigue is a frequent, debilitating symptom of inflammatory bowel disease (IBD). Despite this, studies report dissatisfaction among IBD patients regarding how little attention is given to fatigue-related issues during consultations. We performed a pilot randomized controlled trial (RCT) to assess whether a brief, structured, multidisciplinary psychological support program improved fatigue, mood and quality of life indices in patients with quiescent IBD. METHODS: The intervention consisted of three small-group psychoeducational sessions over 6 months. Primary outcomes were effect on fatigue severity and impact scores. Secondary outcomes included effect on depression, anxiety, somatization scores, generic and disease-specific quality of life. RESULTS: Twenty-three patients were enrolled, 10 in the intervention arm and 13 controls. Mean fatigue severity and impact scores improved for patients in the intervention group (by 14.5-13.1 and 49.7-45.8, respectively), and worsened in controls (by 11.5-12.6 and 33.5-35 respectively). Mean Short Form 36 (SF-36) scores for role limitations due to physical health decreased from 44.4 to 38.9 in the intervention group, but increased from 44.2 to 51.9 among controls. Energy scores in the intervention group improved from 17.8 to 26.6, but only from 31.4 to 31.7 among controls. Short IBD questionnaire scores improved in both groups, from 46.2 to 45.2 in controls compared with 44.4-40 in the intervention group. DISCUSSION: In this small pilot RCT, positive effects were demonstrated on fatigue, energy levels and other quality of life outcomes. Larger, adequately powered studies with longer follow up are required.ClincialTrials.gov identifier: NCT02709434.